1. Field of the Invention
This invention relates to new 10-substituted camptothecin derivatives possessing anti-tumor activity (including carcinostatic activity) and to processes for the preparation of such derivatives. More particularly, this invention relates to new 5-R.sup.1 -7-R.sup.2 -camptothecin derivatives carrying a substituent R.sup.3 in the 10-position thereof and possessing anti-tumor activity with a low level of toxicity as well as processes for the preparation of 10-substituted camptothecin derivatives.
2. Description of the Prior Art
Camptothecin is a cytotoxic alkaloid isolated from leaves and barks of Camptotheca accuminata (Nyssaceae), a plant native to China, which has a pentacyclic structure consisting of a characteristic fused 5-ring system of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action and its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itself for clinical treatments is significantly limited because of high toxicity.
Accordingly, a number of attempt have been made to reduce toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives. The chemical modifications so far reported are mainly about the rings D and/or E of camptothecin, but the results of such modifications revealed only failure in maintaining expected anti-tumor activity and poor improvement in toxicity [J. Med. Chem., 19 (1976), 675]. From the chemotherapeutic point of view, therefore, it is of importance that the chemical modifications of camptothecin should be restricted in the rings A, B and C without effecting any change in the rings D and E which are conceivable to be one of the essential structural elements for the expression of the above mentioned characteristic biological activities. Except for a method for functionalizing 12-position of camptothecin reported in 1976 which comprises a series of troublesome conversion and purification operations starting with nitration at 12-position [P. Pei-chuang et al., Hau Hsueh Pao 33 (1975); Chem. Abstr. 84 (1976) 115629p], no success was reported until 1979 in connection with chemical functionalization of camptothecin in a moiety involving the rings A, B and C. This is probably ascribable to the reasons that camptothecin itself is only sparingly soluble in various organic solvents and that camptothecin possessing the nature of heterocyclic rings in its molecule is resistant to the so-called electronphilic reactions conventionally carried out on aromatic rings. In the present status such obstacles strongly refuse chemical modifications of camptothecin contemplated on the desk for preparing new classes for derivatives thereof.
Under the above mentioned circumstances, the present inventors previously found together with co-workers processes for introducing (1) hydroxymethyl group into 7-position, (2) hydroxy group into 5-position and (3) an alkyl or aralkyl group into 7-position of camptothecin efficiently in a single step, and prepared a great number of new camptothecin derivatives possessing anti-tumor activity with slight toxicity from 5-and/or 7-substituted camptothecin obtained according to the above processes, by chemical modification of the 5- and/or 7-substituent (Japanese Laid-open patent application. Nos. Sho. 56-12391, 56-12392, 56-12393, 56-12394, 56-158786, 57-116075 and 57-116076; U.S. Pat. No. 4,399,276 and 4,399,282; and DOS No. 30 26 172). However, the sorts of camptothecin derivatives prepared according to these processes are still limitative.
Noteworthy in recent years is that 10-hydroxycamptothecin isolated from Camptotheca acuminata was reported to be lower in toxicity than camptothecin itself but higher in anti-tumor activity (a certain medical magazine in China, 1978). For further extensive researches on the relation between substituents in camptothecin derivatives and anti-tumor activity and/or toxicity, therefore, there is still a great demand in this art for developing further new classes of camptothecin derivatives possessing a low level of toxicity while maintaining the inherent anti-tumor activity by chemical modifications of camptothecin itself or derivatives thereof in a simple manner.